Numerous techniques have been developed for circulating the blood of a patient outside the body in an "extracorporeal" circuit and then returning it to the patient during a surgical procedure. For example, in dialysis for patients with kidney failure, blood is circulated extracorporeally and contacted with a large membrane surface separating the blood from a dialysate solution, and urea and other blood chemicals are migrated across the membrane to cleanse the blood, which is then returned to the patient. In ex vivo organ perfusion, such as liver perfusion for patients with liver failure, blood is circulated extracorporeally and perfused through a donor organ, typically a pig liver in the case of liver perfusion, before returning it to the patient. In cases of thermal treatment, blood is circulated out of the body and through a heat exchanger and returned to the body. In heart surgery, either or both ventricles of the heart may be isolated and surgically repaired while making use of the patient's lungs during the surgery. In left monoventricular surgery, the left ventricle is isolated for surgery by cannulating the left atrium into an extracorporeal circuit which pumps the blood into a cannulated femoral artery or other arterial source to the arterial bed. In biventricular surgery, the right ventricle is isolated for surgery by cannulating the right atrium and feeding the blood extracorporeally to the pulmonary artery, and the left ventricle is isolated by cannulating the left atrium and feeding the oxygenated blood extracorporeally to a femoral or other artery for perfusion of the arterial bed.
Another example of extracorporeal circulation is cardiopulmonary bypass ("CPB"), the procedure of mechanically bypassing both the heart and lungs to allow the whole heart to be isolated for surgical repair. A CPB machine, consisting of a number of independent and discrete components linked together by plastic tubing, assumes the function of the heart and lungs by oxygenating the blood of the patient, returning the oxygenated blood to the body, and pumping it through patient's circulatory system. More particularly, in CPB the patient's inferior and superior venae cava are cannulated and the blood is ducted from the patient to a venous reservoir in the CPB circuit. From the venous reservoir, this circuit then connects to a pump which circulates the blood. The blood is then oxygenated by being pumped through a gas exchange reservoir ("oxygenator") where oxygen is added and carbon dioxide is removed from the system. The next CPB element is the heat exchanger where the temperature of the blood can be altered and controlled. This device is typically coupled in parallel to the oxygenator. The last element of the extracorporeal circuit is typically a filter used to eliminate particulate matter accumulated in the extracorporeal system. The oxygenated blood then enters the body of the patient through another cannula in the arterial system. Other elements which are part of the CPB system but operated in parallel to the circuit include systems used to retain suctioned blood in the operative field to return to the patient ("cardioplegia") and systems to filter and concentrate the cells also to be given to the patient through the CPB circuit (cell savers or hemoconcentrators).
Extracorporeal circulation of a patient's blood causes bleeding and thrombotic complications, fluid retention and temporary dysfunction of every organ system. The reason is because contact of the blood with the foreign surfaces of the extravascular circuit triggers a massive defense reaction in blood proteins and cells that has been called "the whole body inflammatory response." The problem has especially been documented in connection with CPB surgery. See Blackstone E. H. et al "The Damaging Effects of Cardiopulmonary Bypass," in Wu K. K., Roxy E. C. (eds), PROSTAGLANDINS IN CLINICAL MEDICINE: CARDIOVASCULAR AND THROMBOTIC DISORDERS, Chicago, Yearbook Medical Publishers, 1982, pp. 355-369, incorporated herein by reference.
In the "whole body inflammatory response" platelets are activated by contact with surfaces other than the endothelial cells that line the circulatory system of the body. The activated platelets adhere to non-endothelial cell surfaces, then aggregate and release granule contents and synthesize powerful vasoconstrictor substances. These granules in turn release coagulation proteins, substances that increase capillary permeability and attract neutrophils, substances that enhance platelet adhesion and aggregation, and numerous other substances including vasoconstrictors norepinephrine, serotonin and histamine, and potent hydrolases and proteases. These granule products contribute to systemic inflammatory response associated with extracorporeal blood circulation. Deficiencies of platelet number and function after extracorporeal circulation such as in CPB are a major cause of postoperative bleeding. Neutophils are strongly activated by extracorporeal circulation and release many cytotoxic chemicals and powerful enzymes that mediate much of the inflammatory response associated with extracorporeal circulation. Interstitial fluid accumulates rapidly especially during CPB caused by increased capillary permeability, increased central venous pressure and decreased colloid osmotic pressure due to hemodilution. Vasoactive substances released by the defense reaction cause endothelial cells or vascular smooth muscle cells to contract or relax or alter the contractile strength of cardiac myocytes. Circulation of these substances contributes to fluid retention and the whole body inflammatory response. Microemboli including fibrin, denatured protein and platelet aggregates too small for capture by extracorporeal circulation filters bombard the organs and may be responsible in CPB procedures for subtle central nervous system deficits that afflict over 50% of patients and can persist for more than a year.
In order to prevent blood from clotting in extracorporeal circulation procedures, heparin is systemically administered to the patient, but heparin does not prevent the whole body inflammatory reaction. This is because heparin acts primarily at the end of the coagulation cascade and does not prevent activation of at least five plasma protein systems (contact; intrinsic coagulation pathway; extrinsic coagulation pathway; complement; and fibrinolysis) and five blood cells (platelets, neutrophils, monocytes, endothelial cells and lymphocytes) which act to produce more than two dozen vasoactive substances that alter the vascular tone, capillary permeability and cardiac myocyte contractability. Heart-lung machines often have heparin coated surfaces, and these seem to be thromboresistent, apparently because they are instantly covered with layers of plasma proteins which isolate the surface from direct contact with flowing blood. However, all attempts to produce nonthrombogenic synthetic materials have failed. Although some materials are less thrombogenic than others, all activate blood elements to initiate clotting and activate the body's defense reaction. See generally, L. Henry Edmonds, "Breaking the Blood-Biomaterial Barrier," presented at the Cardiovascular Science and Technology Conference, Washington, D.C., Dec. 9, 1994 (reprints available from the author at Dept. of Surgery, 4 Silverstein, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pa. 19104), and J. H. Gorman and L. Henry Edmunds, Jr., "Blood Anesthesia for Cardiopulmonary bypass," J. CARD. SURG. 1995, 10, 270-279, both incorporated herein by reference.
Although the search for a bioactive material that does not activate blood elements during extracorporeal circulation such as CPB is one approach, another is research into bioactive substances that can temporarily prevent the initial reactions of blood elements that are activated by direct contact with the proteins adsorbed onto biomaterials. An example is the work reported in "Iloprast and Echistatin protect platelets during simulated extracorporeal circulation," Bernabel A., et al., ANN. THORAC. SURG. 1995; 59:149-153.
Only the endothelial cell lining of the blood vessels in the circulatory system is nonthrombogenic. It achieves this property by active metabolic processes and its ability to attract only specific plasma proteins when appropriate. The endothelial cells continuously produce and release local bioregulatory factors into the blood stream and vessel walls. In the normal vessel these endogenous factors regulate platelet adhesion and aggregation in the blood stream (clotting) while in the vessel wall they inhibit neutrophil adhesion and chemotaxis (inflammation), and maintain vascular tone (vasodilation). Nitric oxide (NO), an endothelium derived relaxing factor, plays a key role in regulating platelet activation. See "Endogenous And Exogenous Nitric Oxide Protect Intracoronary Thrombosis And Reocclusion After Thrombolysis", Yao S., et al., CIRCULATION, 92:1005-1010, 1995. Endothelial cells synthesize nitric oxide from nitrogen atoms of the amino acid L-arginine through the action of a soluble enzyme Pharmacological Reviews 43:109, 1991!. This vital biochemical system, called the L-arginine/nitric oxide pathway, also exists in other cells and has been shown to modulate the reactivity of stimulated platelets, neutrophils and smooth muscle cells. In the blood stream, nitric oxide is inactivated by hemoglobin, which explains its short half-life and localized effects. L-arginine and nitric oxide donor substances have been used to supplement blood cardioplegia and reperfusion to preserve endothelial cell function and reverse postcardioplegia contractile dysfunction to hearts exposed to global myocardial ischemia during cardiac surgery. See "Augmentation of Microvascular Nitric Oxide Improves Myocardial Performance Following Global Ischemia," Hammon J. W. et al., J. CARD. SURG., 1995, 10 (Supp), 423-427. Nitric oxide has been under limited investigation as an approach to reduce platelet aggregation by artificial surfaces during CPB. See, "Inhibition Of Surface-Induced Platelet Activation By Nitric Oxide," Sly K., et al., ASAIO Journal 1995;41:M394-M398, in which nitric oxide was added to the oxygenator sweep gas of a membrane oxygenator of a CPB model and some reduction of platelet aggregation was seen, along with decreased rates of platelet aggregation.